Guidelines Summary

The Surviving Sepsis Campaign (SSC) published International Guidelines for Management of Sepsis and Septic Shock in 2016. These guidelines serve as an update to the previously printed 2012 guidelines.
[42] A number of significant updates have been made to the guidelines for the management of septic shock between 2012 and 2016. The 2012 SSC guidelines, like their predecessors, reflected the Early Goal-Directed Therapy (EGDT) protocol established by the Rivers trial.
[26] The EGDT protocol was a single urban-center trial published in 2001, which demonstrated that using a protocol that featured aggressive resuscitation (titrated to certain physiologic values such as mean arterial pressure, central venous pressure, and mixed venous oxygen saturation) along with early antibiotic initiation led to absolute risk reduction in mortality of up to 16% of patients with severe sepsis or septic shock. One of the criticisms of EGDT, however, was identifying which intervention conferred a survival benefit.

In 2014, the ProCESS multicenter trial sought to compare the EGDT protocol versus a novel protocol (using noninvasive monitoring) versus usual care as directed by the treating physicians.
[35] The ProCESS trial found that among patients with septic shock, there was no significant difference in all-cause mortality at 60 days, 90 days, or 1 year. Furthermore, there was no significant difference in the need for organ support. The ProCESS trial, while having impactful results, was primarily performed with patients enrolling at academic medical centers. The ARISE trial of 2014 also showed no reduction in all-cause mortality at 90 days while enrolling 1600 randomized patients with severe sepsis or septic shock at 51 academic and nonacademic medical centers in 5 different countries.
[34] A third trial, known as the OPTIMISE trial, was a multicenter randomized, observer-blinded trial held in the United Kingdom.
[36] This trial sought to evaluate the outcome of EGDT 30-day mortality in high-risk gastrointestinal surgical patients as the primary outcome. The OPTIMISE trial found no outcome benefit with EGDT versus usual care. Furthermore, OPTIMISE found no difference between EGDT and usual care on secondary outcome measures, such as morbidity on day 7, infection, critical care–free days, all-cause mortality at 30/180 days, and length of stay.

The aforementioned trials are three prime examples of investigations on whether or not EGDT as the method of initial resuscitation is truly beneficial. Because of the evidence, the SSC 2016 campaign revisited their guidelines to include the findings of such trials. The 2016 guidelines
[42] are paraphrased below.

A. Initial resuscitation

Septic shock is a medical emergency. Intravenous fluid resuscitation for sepsis-induced hypoperfusion should consist of at least 30 mL/kg of intravenous crystalloid fluid being given within the first 3 hours. After initial fluid resuscitation is performed, additional fluids should be given based on frequent assessment of the patient's hemodynamic status. Dynamic over static variables are favored in assessing patient response to fluid resuscitation, with a particular goal of keeping an initial target mean arterial pressure of 65 mm Hg in patients with septic shock requiring vasopressors. Normalizing elevated lactate levels is also recommended, as lactate levels serve as a marker of tissue hypoperfusion.

B. Screening for sepsis and performance improvement

Hospitals and hospital systems should have a performance improvement program in place for sepsis, including screening practices.

C. Diagnosis

It is recommended that appropriate microbiologic cultures be collected prior to antibiotic administration for patients with suspected sepsis/septic shock.

D. Antimicrobial therapy

Empiric broad-spectrum intravenous antibiotics should be initiated within 1 hour for both sepsis and septic shock. The antibiotics should cover all likely pathogens (including bacterial and potentially fungal or viral coverage). Upon discovery of the offending organism and the corresponding antibiotic sensitivities result, the antibiotic spectrum should be narrowed. However, sustained antibiotics should not be given in shock states of known noninfectious origins (eg, distributive shock due to pancreatitis).

If combination antibiotic therapy is used for septic shock, the recommendation is to discontinue the combination therapy within the first few days in response to clinical improvement and/or evidence of infection resolution. This is recommended in both culture-positive and culture-negative infections. Antimicrobial treatment of 7-10 days is adequate for most serious infections associated with septic shock; however, certain infections may require longer clinical courses, such as the case for patients who have a slow clinical response, undrainable foci of infection, bacteremia with methicillin-resistance Staphylococcus aureus (MRSA), some fungal and viral infections, or immunologic deficiencies.

E. Source control

Rapid identification or exclusion of an anatomic nidus of infection is recommended. Any required intervention to eradicate the source of infection should be done as soon as possible. This incudes prompt removal of intravenous devices such as central lines.

F. Fluid therapy

Crystalloids are the intravenous fluids of choice for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock. Hydroxyethyl starches for intravascular volume replacement or gelatins are not recommended choices for fluid resuscitation.

G. Vasoactive medications

Norepinephrine is the first-choice vasopressor for patients in septic shock. Either vasopressin or epinephrine can be added to norepinephrine to raise the mean arterial pressure to target. Dopamine is another alternative vasopressor agent to norepinephrine in patients with low risk of arrhythmias, although this is a weak recommendation with low quality of evidence. Low-dose dopamine is not recommended for renal protection.

Dobutamine is another vasopressor that is recommended in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents. The dose of dobutamine should be titrated to the specific endpoint of tissue perfusion. The dose should also be reduced in the setting of worsening hypotension and arrhythmias. Blood pressure should be monitored via an arterial line when using vasopressors.

H. Corticosteroids

The guidelines suggest against using intravenous hydrocortisone to treat septic shock in patients adequately treated with vasopressors and fluid resuscitation. If this is not possible, 200 mg of intravenous hydrocortisone is recommended per day to help augment blood pressure to goal.

I. Blood products

It is recommended that packed red blood cell transfusion occur when the hemoglobin is below 7.0 g/dL. Red blood cell transfusion should occur only when the hemoglobin concentration decreases to less than 7.0 g/dL in adults in the absence of acute hemorrhage, myocardial ischemia, or severe hypoxemia. Erythropoietin is not recommended for the treatment of sepsis-related anemia.

J. Immunoglobulins

The use of intravenous immunoglobulins is not recommended in patients with sepsis or septic shock.

K. Blood purification

There is no recommendation regarding the use of blood purification techniques.

L. Anticoagulants

Antithrombin is not recommended for the treatment of sepsis and septic shock. There is no recommendation for the use of thrombomodulin or heparin for the treatment of sepsis or septic shock.

M. Mechanical ventilation

A tidal volume of 6 mL/kg for predicted body weight compared with 12 mL/kg in adult patients with sepsis-induced acute respiratory distress syndrome (ARDS) is recommended. The upper limit goal for plateau pressures is 30 cm water for sepsis-induced ARDS. Higher positive end-expiratory pressure (PEEP) and recruitment maneuvers in adult patients is preferred in sepsis-induced moderate-to-severe ARDS. While on the ventilator, patients should be positioned between 30° and 45° to limit the risk of aspiration. Spontaneous breathing trials should be initiated for patients who are ready to be weaned off the mechanical ventilator.

With regard to patient positioning, prone over supine position is recommended in adult patients with sepsis-induced ARDS and ratio of arterial oxygen saturation to fraction of inspired oxygen (PaO2/FIO2 ratio) of less than 150. Neuromuscular agents for 48 hours are also recommended with the aforementioned ratio. The campaign recommends against using high-frequency oscillatory ventilation in adult patients with sepsis-induced ARDS

If there is no evidence of tissue hypoperfusion, a conservative fluid strategy is preferred for patients with established sepsis-induced ARDS. ß-2 agonists are not recommended for sepsis-induced ARDS without bronchospasm. Finally, routine use of pulmonary artery catheters (Swan-Ganz) for hemodynamic measurements is not recommended in sepsis-induced ARDS.

N. Sedation and analgesia

Conscious or intermittent sedation should be minimized in mechanically ventilated sepsis patients.

O. Glucose control

In septic ICU patients, there should be a protocol for insulin dosing when two consecutive blood glucose levels are greater than 180 mg/dL, with a target of 110-180 mg/dL. Furthermore, glucose levels should be monitored every 1-2 hours until stabilization of insulin infusion and glucose levels.

P. Renal replacement therapy

Continuous or intermittent forms of renal replacement therapy can be used to facilitate management of fluid balance in hemodynamically unstable septic patients, or in septic patients with acute kidney injury who have an increase in creatinine/oliguria.

Q. Bicarbonate therapy

Sodium bicarbonate therapy may improve hemodynamics in patients with lactic acidemia and a pH of less than 7.15.

R. Venous thromboembolism prophylaxis

In the absence of contraindications, pharmacologic prophylaxis against venous thromboembolism (VTE) should be initiated. Low molecular weight heparins are preferred over unfractionated heparin for VTE. Whenever possible, a combination of pharmacologic and mechanical prophylaxis is recommended. However, when pharmacologic prophylaxis is not possible (eg, hemorrhagic shock, intracranial bleeding), mechanical VTE prophylaxis is suggested.

S. Stress ulcer prophylaxis

If a patient has risk factors for gastrointestinal bleeding, stress ulcer prophylaxis should be given with either proton pump inhibitors or histamine-2 receptor antagonists. If a patient does not have risk factors for gastrointestinal bleeding, stress ulcer prophylaxis is not recommended.

T. Nutrition

Early initiation of enteral feeding instead of complete fasting or intravenous glucose is recommended only in critically patients with sepsis or septic shock who can be fed enterally. Feeds should either be early tropic/hypocaloric or early full enteral feeding. Parenteral nutrition is not recommended as a stand-alone feeding modality or in combination with enteral feedings. Parenteral nutrition is also not recommended over the first 7 days in critically ill sepsis/septic shock patients who cannot be fed enterally. Omega-3 fatty acids as immune supplements are not recommended in this patient population.

In addition, monitoring of gastric residual volumes is recommended in those patients on enteral feeds at high risk of aspiration. Postpyloric feeding tubes should be placed in critically ill patients with sepsis or septic shock if they have feeding intolerance or are at high risk for aspiration. Prokinetic agents may also be helpful in this patient population if they have feeding intolerance.

U. Setting goals of care

Goals of care and prognosis should be discussed with patients and their families or healthcare proxies. The goals should be addressed as early as possible while being incorporated into treatment and end-of-life planning, using principles of palliative medicine where appropriate.

Microcirculatory abnormalities in distributive shock. Each image represents a venule (large, curved tube) and 2 capillaries (smaller tubes) and demonstrates the 2 main capillary flow patterns found in each class of microcirculatory abnormality, as they occur in distributive shock. This classification system was introduced by Elbers and Ince. Elbers P, Ince C. Bench-to-bedside review: mechanisms of critical illness—classifying microcirculatory flow abnormalities in distributive shock. Crit Care. July 19 2006;10(4):221.

Ultrasound clip demonstrating a collapsing inferior vena cava (IVC) on inspiration. A change in IVC diameter with respiration of at least 12-18% has been associated with fluid responsiveness (defined as an increase in cardiac output of >15% after a fluid bolus).

Lung ultrasound image over one lung zone showing the A-line pattern. This represents normal aeration and absence of pulmonary edema. A patient who demonstrates this pattern in conjunction with an inferior vena cava diameter that shows respirophasic variation of at least 12-18% will likely be fluid responsive.

*In cardiogenic shock due to a mechanical defect, such as mitral regurgitation, forward cardiac output is reduced, although the measured cardiac output may be unreliable. Large V waves are commonly observed in the pulmonary capillary wedge tracing in mitral regurgitation.

Disclosure: Received income in an amount equal to or greater than $250 from: Masimo, Edwards Lifesciences, Cheetah Medical<br/>Received honoraria from LiDCO Ltd for consulting; Received intellectual property rights from iNTELOMED for board membership; Received honoraria from Edwards Lifesciences for consulting; Received honoraria from Masimo, Inc for board membership.